PROJECT SUMMARY. Alzheimer's disease (AD) currently affects ~ 47 million people worldwide and is the third leading cause of death after cancer and heart disease. At present, definitive confirmation of AD occurs only during autopsy. Being able to detect small concentrations of AD biomarkers in the blood and follow the change of the concentration over time would not only enable early detection of the disease, but also support current efforts to develop early treatments and prevention therapies. Currently biomarkers such as amyloid beta and tau are detected in cerebrospinal fluid (CSF), which is a relatively invasive procedure that can lead to low compliance and significant side effects in some subjects, limiting the acquisition of repeated samples that would be informative in longitudinal studies. If biomarkers could be reliably detected in small quantities of serum or plasma, tests could be made more routine, available, less expensive, and with minimal risk. Due to the blood-brain barrier, however, blood does not come into direct contact with the brain. As a result, biomarkers which have been identified in CSF have not been shown in a robust and reliable way to be present in measurable quantities in serum/plasma that reflect the deposition of pathology in brain. We have recently developed a technique known as FLOWER (Frequency Locked Optical Whispering Evanescent Resonator) that can detect low concentrations of molecules down to the single molecule limit without requiring the use of labels such as fluorescent or radioactive tags. We would like to evaluate the ability of FLOWER to test for the AD biomarkers, amyloid beta and tau, in both CSF and serum. There are potential benefits for applying FLOWER to both types of samples. For CSF, FLOWER offers greater sensitivity that could be more reliable and robust, cheaper, and easier to reproduce across labs. With regards to serum/plasma, FLOWER offers the potential to provide a way to measure these markers using samples that are easier to obtain and with low risk to participants, especially for repeated measurement. The serum/plasma detection can be directly assessed against the CSF markers to help validate the measures with established markers that reflect deposition in brain. We propose using FLOWER as a more sensitive way of detecting biomarkers such as amyloid beta and tau fragments in cerebrospinal fluid as well as a method to detect whether low concentrations of amyloid beta and tau fragments exist in serum/plasma that are associated with the CSF brain-based measurements. We will then evaluate these results in relation to clinical and pathological disease state from individuals with Alzheimer's dementia, mild cognitive impairment (MCI), and age-matched healthy elderly controls. In the future, as a follow-up to this work, there is added value in having participants with known pathology for diagnosis after autopsy. If antemortem cognitive testing or screening is available near time of death, this could provide added value to test the measures in CSF and blood against clinical measures of severity.